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Novel Treatent for Lung Cancer

David R. Gandara, MD Director, Thoracic Oncology Group, Senior Advisor to the Director, UC Davic Comprehensive Cancer Center; Sacramento, California

David R. Gandara, MDUniversity of California Davis Comprehensive Cancer Center

Novel Strategies to Personalize Therapy in Advanced Non‐Small Cell Lung Cancer (NSCLC)

Disclosures

• Research Grants: AZ/Medi, BMS, Clovis, Genentech, JNJ, Lilly, Merck, Novartis

• Consultant: AstraZeneca, Boehringer-Ingelheim, Celgene, Clovis, Genentech, Guardant Health, Lilly, Merck, Novartis, Perigrine, Pfizer, Response Genetics, Synta

“Eating an Elephant:An analogy to defeating Lung Cancer

“ If you want to eat an elephant, you need a strategy”

“ If you try to do it in one bite, you willchoke on it”

M. Vestager. – May 25, 2015EU Antitrust Chief& Danish politician

“When eating an elephant, take 1 bite at a time”Creighton Adams, Jr, GeneralChief of Staff, US Army 1972

Requisites: Transition from Empiric to Personalized Cancer Therapy (Biomarker-Driven)

Biomarker-Driven & Personalized Therapy

Empiric Therapy

Tumor Molecular Profiling to identify drug targets

(adequate tumor tissue)

Drugs against the Molecular Targets

Predictive Biomarkersfor the drugs

Gandara et al: Clin Lung Cancer, 2012

Clinical Trial Designsthat define the activity

of a drug against it’s target(predictive biomarker)

“Targeted Therapy”Chemotherapy

Checkpoint ImmunotherapyGenomics‐driven TKIs:

‐EGFR‐ALK‐ROS1

Anti‐PD‐1 and PD‐L1

(Anti‐CTLA‐4)?

What are the available “Tools” to facilitate Individualized Therapy in advanced stage NSCLC?

The Questions: How do we optimize therapy in individual patients? How do we account for tumor evolution over time and after targeted therapy?

How do we best integrate new diagnostic testing platforms for targeted therapy or immunotherapy to achieve optimal results? (Next Gen Sequencing [NGS] in

tissue or cell free[cf]DNA in plasma)

HistologicSubtyping for Chemotherapy

Li, Mack, Kung, Gandara . JCO. 2013 (adapted from Pao et al).

NSCLCas one disease

What does this mean from the Patientand Physician standpoint?

Evolution of NSCLC Subtyping from Histologic to a Multitude of Genomically‐defined Subsets

Lung Cancer

100 patients with advanced stage Lung Cancer:They all look alike, but they are not

Non‐small cell lung cancer (NSCLC)

100 patients with advanced stage Lung Cancer:Non‐small Cell (NSCLC) versus Small Cell Lung Cancer (SCLC)

SCLC

86 patients with advanced stage NSCLC:They all look alike, but they are not

43 y/o femaleNever‐Smoker

Adenoca

74 y/o maleSmoker

SquamousFGFR fusion

In 2015: •Oncologists would conclude that these patients have very different malignancies•Oncologists would conclude that these patients have vastly different therapeutic options

56 y/o femaleFormer Smoker

AdenocaKRAS mt

EGFR mt

52 y/o maleFormer Smoker

AdenocaALK fusion

86 patients with advanced stage NSCLC:Breakdown by Histologic Subtype

Adeno Large cell /NE SCC

86 patients with advanced stage NSCLC:Therapeutic Implications of Non‐SCC versus SCC

Non‐SCC (Adeno+ Large Cell) SCC

Two therapeutic agents contraindcated in SCC:• Pemetrexed: reduced efficacy in SCC• Bevacizumab: increased toxicity in SCC

JMDB: Pemetrexed/Cisplatin vs Gemcitabine/Cisplatin in NSCLC with Pre-defined Analysis by

Histologic Subtype

•Previously Untreated•Stage IIIB or IV •ECOG PS 0-1• N=1,725

R

Pem/Cisplatin

Gem/Cisplatin

1. Adenocarcinoma

2. Large Cell

3. Squamous Cell

1. Adenocarcinoma

2. Large Cell

3. Squamous Cell

Scagliotti, Gandara et al. JCO 26: 3543, 2008

Scagliotti, Gandara et al. JCO, 2008.

JMDB: Pemetrexed/Cisplatin vs Gemcitabine/Cisplatin in Advanced NSCLC

No differences between regimens in the overall patient population

100

80

60

40

20

0

0 4 8 12 16 20 24 28 32Time Since Randomization (Months)

Pem-Cis

Gem-CisOverall Survival (%

)

HR (adj)(95% CI): 0.81 (0.70, 0.94); P=0.005

Median OS, months:Pem‐Cis: 11.8Gem‐Cis: 10.4

Non-squamous

100

80

60

40

20

0

0 4 8 12 16 20 24 28 32Time Since Randomization (Months)

Pem-CisGem-Cis

Overall Survival (%

)

HR (adj)(95% CI): 1.23 (1.00, 1.51); P=0.05

Median OS, months:Pem‐Cis: 9.4Gem‐Cis: 10.8

Squamous

Scagliotti, Gandara et al. JCO, 2008.

JMDB: Pemetrexed/Cisplatin vs Gemcitabine/Cisplatin in NSCLC with Pre-defined Analysis by Histologic Subtype

• Pemetrexed regimen superior in Non‐squamous histology• Gemcitabine regimen superior in Squamous histology

Thymidylate Syntase (TS) mRNA expression by Histology:Squamous (SCCA) versus Adenoca (AC)

p<0.001TS

(Reference <2.33 for

pemetrexed)

% Below Reference

Level

NSCLC-Total 42%

Adenoca 46%

SCCA 26%

Maus MK, Gandara DR, et al. J Thorac Oncol. 2013;8(5):582‐6.

N=1,671

TS is a molecular target of PemetrexedHigh TS is indicative of Pemetrexed resistance

Thus SCCA is relatively resistant to Pemetrexed by comparison with Adenocarinoma

However, TS remains a research tool (not fully validated)

60 patients with advanced stage NSCLC:Non‐SCC Histology

Non‐SCC (Adeno+ Large Cell)

Adeno/Large CellALKEGFR

EGFR mutation ALK ROS RET HER2BRAF KRAS

KRAS

KRASROS1

“The Big 3”

60 patients with advanced stage Non‐SCC NSCLC: Breakdown by Oncogene Subtype

Target(s) EGFR EGFR EGFR(~ErbB family)

ALKROS1

Drug Gefitnib(1st Gen)

Erlotinib(1st Gen)

Afatinib(2nd Gen)

Crizotinib(1st Gen)

Response(average) ~60‐75% ~60‐75% ~60‐75% ~60‐70%

Progression Free

Survival~10 months ~10 months ~11 months ~11 months

EGFR mutation ALK ROS1

‘Targeted’ Therapy is most effective when directed toward patients with cancers expressing the target:

‘Oncogenic Addiction’

Lynch et al. N Engl J Med. 2004;350:2129‐2139.

EGFR TKIs EGFRMutationsAbout 12% of NSCLCIn US (40% in E. Asia)

Most common in:• Adenocarcinoma

(~BAC)• Never‐smokers• East Asians• Females• Younger patients

But clinical characteristicsare insufficient to

select 1st line therapy

IPASS: Gefitinib vs Chemotherapy in East Asian Patients with Advanced Lung Adenocarcinoma

*All East Asian80% female94% never‐smokers

Mok et al: NEJM, 2009

IPASS* (TKI Gefitinib versus Chemotherapy): Impact of EGFR mutation

Progression‐free survival in EGFR mutation positive & negative cancers

EGFR mutation positive EGFR mutation negative

Treatment by subgroup interaction test, p<0.0001

HR (95% CI) = 0.48 (0.36, 0.64) p<0.0001

Gefitinib (n=132)Carboplatin / paclitaxel (n=129)

HR (95% CI) = 2.85 (2.05, 3.98)p<0.0001

0 4 8 12 16 20 240.0

0.2

0.4

0.6

0.8

1.0

Prob

abili

ty o

f pro

gres

sion

-free

sur

viva

l

0 4 8 12 16 20 240.0

0.2

0.4

0.6

0.8

1.0

Prob

abili

ty o

f pro

gres

sion

-free

sur

viva

l

Gefitinib (n=91)Carboplatin / paclitaxel (n=85)

Months Months

Mok TS, et al. N Engl J Med. 2009;361:947-957.

• Clinical characteristics are insufficient for selection of 1st line EGFR TKI Therapy

• Front line EGFR TKI should be restricted to EGFR MT+ patients

*All East Asian patients, 80% female, 94% never-smokers

The Growing List of Guideline Recommendations: Too Many Mutations for a Single Test

http://www.nccn.org/professionals/physician_gls/pdf/nscl.pdfNote: EGFR mutations too rare (<3.6%) to be routinely tested in squamous cell carcinoma

From Li, Gandara et al. JCO. 2013.

Evolution of Biomarker Testing in Clinical Practice: Past, Current & Future

Near‐Future Approach (Patient‐Based Therapy):Genomic profiling by high throughput next generation sequencing

for decision‐making in individual patients

1. HistomorphologicalDiagnosis: Cancer

Evolving Approach (Target‐Based Therapy V2.0):Multiplexed molecular tests with increased sensitivity & output

for decision‐making in individual patients

Current Approach (Target‐Based Therapy V1.0):Single gene molecular testing for decision‐making in individual

patients

2. Molecular Diagnosis:Extract tumournucleic acids:

Archival cancer specimens

Archival FFPE tumourspecimens

Macro‐ or Micro‐dissection of

Tumours

DNA and RNA

Empiric Approach (Past)(Compound‐Based Therapy):

Clinical‐histologic factors to select drugs for individual patients

Representative technologies:

Single Biomarker Tests:• Sanger DNA Sequencing • RT‐PCR• FISH• IHC

Multiplex, Hot Spot Mutation Tests:• PCR‐based SNaPshot• PCR‐based Mass Array SNP• Sequenom

Initial High‐Throughput Technologies:• SNP/CNV DNA microarray• RNA microarray

Next‐Generation Sequencing (NGS):• Whole Genome or Exome Capture Sequencing (DNA)• Whole or Targeted Transcriptome Sequencing (RNA)• Epigenetic profilingPlasma cfDNA by NGS

RET: Cabozantinib : RR=40%

ALK: 65%RR to Crizotinib:~70% RR to 2° Gen TKI

Ceritinib in resistant cancers

METex14: RR >50% to Crizotinib

HER2mutation:>50% RR to Afatinib;~20% to Dacomitinib

BRAF (V600E): >60% RR to BRAF + MEK

inhibitor combo

Translating Genomic Profiling Data into Therapeutic Strategies(Lung Adenocarcinoma)

KRAS:35% RR to MEK inhibitors +

Chemotherapy

ROS1: 70% RR toCrizotinib

HER2 mutation

EGFR: RR>70%to 1°‐2° Gen TKIs;

~60% RR to 3° Gen TKIsin resistant cancers

Acquired Resistance to Targeted Therapies in Oncogene‐Driven NSCLC: Clinical Practice & Clinical Trials

• Targeted Therapies against Oncogene‐Driven Cancers [EGFR mutation+ (Erlotinib) or ALK fusion+ (Crizotinib)] improve response and PFS when compared with chemotherapy

• Even in these most sensitive cancers, acquired resistance is ~universal, with PFS averaging ~10‐14 months

• New strategies are needed to address acquired resistance and/or to circumvent it

Oncogene‐drivenNSCLC

Gandara, Redman et al: Clin Lung Cancer 2014

Cancer Evolution after Therapy (Acquired Resistance)

Burrell and Swanton: Mol Oncol 2014 & CA Res 2012

(A)

(B)

(*)

Major Clinical Implications• Tumor sampling bias dependent

on which site biopsy obtained• Defining “actionable” mutations

(“Driver” vs “Passengers”)?• Defining mechanism of drug

resistance after therapy?

Variations on Branched Evolution

Truncal mt

Li, Mack, Gandara et al. JCO. 2013 (adapted from Pao et al).

NSCLCas one disease

EGFR

EGFR TKITherapy

Evolution of NSCLC Subtyping from Histologic to a Multitude of Genomically‐defined Subsets:

Emergence of Acquired Resistance after therapy

Acquired Resistance

Mechanisms of Acquired Resistance to EGFR TKIs in EGFR‐mutated Lung Cancers

● At the time of acquired resistance, T790M is found in over 50% of repeat biopsies1

● T790M may not always be the cause of clinical resistance, even when present

● Several bypass mechanisms of resistance, including MET or HER2 amplification, or PIK3CA or BRAF mutation, have now been identified

● SCLC transformation can also occur, but is uncommon‐rare

Camidge et al., Nature Rev Clin Oncol, 2014

•Secondary EGFR mutation (i.e. T790M)

•Bypass signaling via ERBB2

•MET over‐expression

•PIK3CA Mutation/AKT

& Others

Mechanisms of EGFR TKI Resistance & Potential Therapeutic Approached (Selected)

2nd Gen EGFR TKIsi.e. Afatinib/Cetuximab3rd Gen‐ AZ9291, CO1686

Anti‐ERBB2 drugsi.e. Afatinib, Dacomitinib

MET Inhibitorsi.e. Crizotinib

Salulitinib

HSP inhibitorsi.e. Ganetespib

AUY922

i.e. BKM120 (PIK3CA)i.e. MK2206 (AKT)

Camidge et al., Nature Rev Clin Oncol, 2014

Differential Response Rates by EGFR T790M status with AZD9291 but not Afatinib/Cetuximab

Overall RR

T790M+ RR

T790M-RR

Overall PFS

T790M+ PFS

T790M-PFS

Osimertinib--AZD92911 53% 59% 22% NA 11.9 2.8

Rociletinib-CO16862 NA 34% NA NA NA NA

Afatinib-Cetuximab3 29% 32% 25% 4.7 4.6 4.8

NA: Not Available1. P. Janne: ELCC 2015 & R. Govindan: Targ Therapies 2016.1. J. Goldman. IASLC Targeted Therapies 2016 (revised) 2. Y. Janjigian et al. Cancer Disc 2014.

Phase II/III Trial of Afatinib With or Without Cetuximab in 1st-Line Therapy of EGFR-mutated NSCLC (S1403):An Approach to Circumventing Acquired Resistance

PIs: Goldberg, Lilenbaum, Politi.

Afatinib + Cetuximab*

Afatinib*

RANDOMISATION

Stage IIIB‐IV NSCLC with EGFR mutation(E19del, L858R)

1st LineEGFR TKI naive

*at PD: Re‐Biopsy for tumor & cfDNA genomics & PDX development (selected patients)

PD: progressive diseasePDX: patient‐derived xenograft

Genomics analysis (NGS)+ cfDNA analysis

“Re‐biopsy” Strategy for Biomarker Testing in Advanced Stage NSCLC: Looking for changes in

“Actionable” Oncogenes

PulmonologistInterventional Radiologist

Surgeon

Identify Target Lesion

Biopsy

Histology Evaluation

Determine Therapy

Pathologist

OncologistMultidisciplinary

Team (Tumor Board)

Molecular Biomarker Testing

Identify Patient

Referring Physician

Med OncologistThoracic Surgeon

Radiation Oncologist PulmonologistRadiologistPathologist

When Progression Re‐Biopsy

Treat

Determine New Therapy

Adapted from: Gandara: ASTRO/ASCO/IASLC Symposium on Molecular Testing, 2012

Treat

When Progression Re‐BiopsyPlasma cfDNA Plasma cfDNA

Role of “Liquid Biopsy” (Plasma cf DNA) in determining mechanisms of Acquired Resistance

Burrell and Swanton, Mol Oncol 2014

Case Example: Role of Liquid Biopsy in EGFR‐Mutated NSCLC

• 50 y/o woman with EGFR‐mutated adenocarcinoma (E19del)

• Previously treated with the EGFR TKI Erlotinib with good response for 1 year

• Now progressive disease (PD) in lung, liver and bones

• A repeat biopsy of a liver lesion is done to determine resistance mechanisms

• Molecular testing on the repeat biopsy shows the original Exon19del mutation but is negative for the resistance mutation T790M

Courtesy of Nir Piled (adapted)

Case Example: 50 y/o woman with EGFR‐mutated lung cancerAt relapse after TKI, re‐biopsy is negative for T790M.

The logical next treatment would then by chemotherapy, not a 3rd Gen EGFR TKI

Plasma Next Gen Sequencing for cell free (cf)DNA

Based on cfDNA analysis, patient started on clinical trial of 3rd gen EGFR TKI AZ9291

Repeat PET scan 2 weeks later: Major Response.

Plasma Next Gen Sequencing for cell free (cf)DNA

At start of AZD9291

2 weeks after

Lessons Learned:• This is an example of intra‐tumor heterogeneity• Re‐biopsy missed T790M; detected by plasma cfDNA

• Cancer cells have mutations that make them recognizable by the immune system (neo‐antigens)

• Theoretically, the higher the mutational load (e.g. through smoking), the greater the immune recognition

• Cancer cells can evade immune surveillance by expressing proteins such as PD‐L1 (a potential biomarker)

• Inhibiting PD‐L1/PD‐1 interactioncan restore anti‐tumor T‐cell activity, leading to immune‐mediated response

Cancer cells evade

T cell killing by

expressing PD-L1

XXPD‐1

PD‐L1MHC I

T cell receptor

Tumor cell

CD8+ CytotoxicT Lymphocyte

(CTL)

Mutation

B7.1

Major PD‐1/PD‐L1 antagonists • Nivolumab (anti‐PD‐1) • Pembrolizumab (anti‐PD‐1)• Atezolizumab (MPDL3280A, anti‐PD‐L1)• Durvalumab (MEDI‐4736, anti‐PD‐L1) • Avelumab (anti‐PD‐L1)

Role of Checkpoint Immunotherapy in Individualized Cancer Patient Care

√√

Spectrum of PD‐1/PD‐L1 Antagonist Activity

• Melanoma• Renal cancer• NSCLC – adenocarcinoma & Squamous cell • Small cell lung cancer • Head and neck cancer • Gastric and GE junction• Mismatch repair deficient tumors (Colon, Cholangiocarcinoma)• Bladder • Triple negative breast cancer• Ovarian• Glioblastoma• Hepatocellular carcinoma • Mesothelioma• Cervical cancer• Hodgkin Lymphoma• Diffuse large cell lymphoma• Follicular lymphoma• T‐cell lymphoma (CTCL, PTCL)• Merkel Cell

Minimal to no activity: • Prostate cancer• MMR+ Colon cancer• Myeloma• Pancreatic Cancer

Active

From NCI review, 10‐2015

Spigel et al: #8008 ASCO 2013.

Are Checkpoint Immunotherapies are“Targeted therapy”?

n= 42 44 34 94 30 53 113 129 65 55 411

Response Rates

Unselected 21% 32% 29% 22% 23% 23% 40% 19% 26% 18% 40%

PD‐L1 + 36% 67% 44% 39% 27% 46% 49% 37% 43% 46% 49%

PD‐L1 ‐ 0% 19% 17% 13% 20% 15% 13% 11% 11% 11% 13%

Intra‐tumoral PD‐L1 expression and response toPD‐1/PD‐L1 blockade

from Callahan: ASCO 2014

Marker positive Strategy:PD-L1+

Phase III Trials of PD-1 therapy compared to Docetaxel in 2nd/3rd-Line Advanced/Metastatic NSCLC

Nivolumab Phase III TrialsStage IIIB/IV Squam (017) NSCLC

non-squamous(057) NSCLC

Docetaxel75 mg/m2 IV

Q3W

Nivolumab3 mg/kg IV

Q2W

Treat until progression or unacceptable toxicity or withdrawal of consent

Overall Survival (OS)

Pembrolizumab Phase III TrialStage IIIB/IV NSCLC


Q3W

Pembro10 mg/kg IV

Q3W



Pembro2 mg/kg IV

Q3W

“All comers” Strategy:(PD-L1+ & PD-L1-)

CheckMate 017: SquamousCheckMate 057: Non-Squamous

POSITIVE POSITIVE

KEYNOTE 010: Squamous + Non-Squamous

Nivolumab Phase III TrialsStage IIIB/IV Squam (017) NSCLC


Q3W

Nivolumab3 mg/kg IV

Q2W



“All Comers” Strategy:(PD‐L1+ & PD‐L1‐)

Phase III Trials of Nivolumuab PD‐1 Therapy Compared to Docetaxelin 2nd Line Advanced/Metastatic NSCLC

CheckMate 017: Squamous

Nivolumab Phase III TrialsStage IIIB/IVNon‐ Squam (057) NSCLC


Q3W

Nivolumab3 mg/kg IV

Q2W



“All Comers” Strategy:(PD‐L1+ & PD‐L1‐)

CheckMate 057: Non‐Squamous

Paz‐Ares et al: LBA109 ASCO 2015Spigal et al: ASCO 2015

Perspective on CheckMate Phase III Trials

Trial 017: Squamous Cell Carcinoma

Trial 057: Non-Squamous Cell Carcinoma

Two positive randomized phase III trials of nivolumab vs. docetaxel,

but very different “Kinetics of Survival Curves”

“Kinetics of Survival Curves (OS)”Trial 017 SQ: Early & continuous separation

Trial 057 Non-SQ: Cross-over but subsequent separation

CheckMate 017: Nivolumab vs Docetaxel in Advanced Squamous NSCLC

Survival benefit of nivolumab was independent of PDL1 expression levelsIn Squamous lung cancer

CheckMate 057: Nivo vs. Doc in advanced Non-Squamous NSCLC

Paz-Ares et al. ASCO 2015, LBA109.OS benefit correlates with PD-L1 expression in this Non-SQ trial.Contrasts with trial 017 in SQ.

OS, PD‐L1 TPS ≥50% Stratum

Analysis cut‐off date: September 30, 2015.

Treatment ArmMedian

(95% CI), moRate at1 y

HRa

(95% CI) P

Pembro 2 mg/kg 14.9 (10.4‐NR) 53.4% 0.54 (0.38‐0.77) 0.00024

Pembro 10 mg/kg 17.3 (11.8‐NR) 58.1% 0.50 (0.36‐0.70) 0.00002

Docetaxel 8.2 (6.4‐10.7) 38.0% — —

aComparison of pembrolizumab vs docetaxel.

Li, Gandara et al: JCO 2013 (adapted from Pao et al)

NSCLCas one disease


Novel Clinical Trial Designs

Evolution of NSCLC Histologic Subsets Genomic Subsets

Li, Mack, Kung, Gandara: JCO 2013

Unmet needs addressed by Master Protocols:

• How to develop drugs for uncommon‐rare genotypes?

• How to apply broad‐based screening (NGS)?

• How to achieve acceptable turn‐around times for molecular testing for therapy initiation? (<2 weeks)

• How to expedite the new drug‐biomarker FDA approval process? (companion diagnostic)


Novel Clinical Trial Designs

S1400 Master Protocol (Lung‐MAP): A Unique Private‐Public Partnership within the NCTN

S1400Master Protocol

S1400Master Protocol

Alliance

ECOG‐Acrin

NRGNCI‐C

SWOG

CT*

TT=Targeted therapy, CT=chemotherapy (docetaxel or gemcitabine), E=erlotinib

S1400: MASTER LUNG-1: Squamous Lung Cancer- 2nd Line Therapy

Biomarker C

TT C+CT CT*

Biomarker Β

TT B CT*

Biomarker A

TT A CT*

Primary EndpointPFS/OS

BiomarkerProfiling (NGS/CLIA)

Biomarker D

TT D+E E*


Non‐MatchDrug

BiomarkerNon‐Match

Multiple Phase II‐ III Sub‐studies with “Rolling Opening & Closure



TT=Targeted therapy, CT=chemotherapy (docetaxel or gemcitabine), E=erlotinib

Each Sub‐Study independent of the others.Each Sub‐study designed for registration of a drug‐biomarker combination.

Self‐sustaining with new Sub‐studies in planning stages.

S1400

TT=Targeted therapy, CT=chemotherapy (docetaxel or gemcitabine), E=erlotinib◊ Archival FFPE tumor, fresh CNB if needed

CT*

AZD4547 CT*

FGFRM: FGFR ampl,mut, fusion

PD-0332991 CT*

CDK4/6M: CCND1, CCND2, CCND3, cdk4 ampl

Common Broad PlatformCLIA Biomarker Profiling◊

HGFM:c-Met Expr

AMG102+E E*

Anti-PD-L1: MEDI4736

Non-match

EndpointPFS/OS

EndpointPFS/OS

EndpointPFS/OS

EndpointPFS/OS

PI3KM:PIK3CA mut

GDC-0032 CT*

LUNG-MAP (S1400): Squamous Lung Cancer- 2nd Line Therapy

• Organizers: NCI‐TMSC, FDA, FNIH, FOCR• Participants: Entire North American Lung Intergroup

(SWOG, Alliance, ECOG‐Acrin, NRG, NCI‐Canada)• Screening: 500‐1,000 patients/year• With 4‐6 arms open simultaneously, anticipate a “hit rate

~65% in matching a patient with a drug/biomarker arm

Interim Endpoint: PFS Primary Endpoint: OS

Genomic Screening(FM one)<2 weeks

PatientRegistrationConsent

TumorCollection

Randomization

Treatment

Assign treatmentArm by marker

NGS/IHC(Foundation Medicine)

InvestigationalTargeted Therapy

Standard of CareTherapy

LUNG-MAP (S1400): Squamous Lung Cancer- 2nd Line Therapy

New TumorBiopsy

(if needed)

GDC‐0032 Vs SoC

PalbociclibVs Soc

AZD4547Vs SoC

GDC‐0032 Palbociclib AZD4547

FGFR1CDK4/61PI3K1

Non‐matchSub‐studies

Nivo/IpiNivolumab

BMN 673Vs SoC

BMN 673

Stage 1

Stage 2

HRD2Checkpoint

Naive1

MEDI4736/Treme

Vs Docetaxel

Checkpoint Refractory2

Matched Sub‐studies

1 Revision #3: Expected September/October 20152 Revision #4: Expected December 2015/January 2016

Updated Lung‐MAP Trial Schema(Expected Fall 2015 with Revs # 3 & 4)

53

• Lung‐MAP amended to 2nd line therapy and beyond to accommodate Nivolumab approval• Pre‐screening added back• Eligibility criteria broadened

“ If you want to eat an elephant, you need a strategy”


M. Vestager. – May 25, 2015EU Antitrust ChiefDanish politician

“Eating an Elephant”: An Analogy to Defeating Lung Cancer

“ If you want to eat(defeat) LUNG CANCER, you needa strategy”


There is no single solution to defeating Lung Cancer.

Like the elephant, it will take many bites.

“Eating an Elephant”: An Analogy to Defeating Lung Cancer

novel treatent for lung cancer david r. gandara, md · novel treatent for lung cancer david r....

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